Chronic ischemic mitral regurgitation (CIMR) remains one of the most vexing, life-threatening clinical problems in cardiac surgery, affects a huge number of patients, leads to congestive heart failure (CHF) which markedly limits life expectancy and functional capacity, and has major adverse implications on U.S. health care costs. Current surgical treatments are not entirely satisfactory, as one-fourth of CIMR repairs may develop severe recurrent mitral regurgitation (MR) within 6 months of operation. Better understanding of mitral function, and the development of more refined procedures based on this enhanced understanding, is clearly needed to improve clinical outcomes. We now have experimental evidence for what appears to be a revolutionary advance in our understanding; direct measurements showing that the mitral valvular-ventricular complex functions as an adaptive control system. In a preliminary experiment, step-function displacements of the posterior mitral leaflet sufficient to cause substantial MR were repeatedly answered within two minutes by geometric alterations of the valvular-ventricular complex to reduce and then eliminate the regurgitation. These findings present a difficult challenge to the traditional view of the mitral valve as a passive system, a view which strongly permeates current medical and surgical practice. The studies outlined in this application employ sophisticated Finite Element modeling and our precise radiopaque marker technology in both acute open-chest and chronic closed-chest ovine experimental models to characterize this newly-discovered control system (its sensors(s), communication network(s), actuator(s), and performance characteristics); to understand the role it plays in CIMR (wherein the valve appears normal, but leaks); and discover which treatments most closely permit continued feedback system control of mitral regurgitation. These studies are made possible by the unique capabilities of our measurement technology to track simultaneously specific transmural LV wall, ventricular, annular, and leaflet anatomical sites with 0.15 mm spatial resolution and 17 msec temporal resolution on a beat-to-beat basis over time, from seconds to months. Relevance: Chronic ischemic mitral regurgitation is a serious problem in cardiac surgery. Current treatments are not satisfactory. This research is likely to lead to improved surgical treatments and medical therapies based on rational criteria, not only for chronic ischemic mitral regurgitation, but for other causes of mitral regurgitation, as well. [unreadable] [unreadable] [unreadable]